Understanding fusion peptide mutations in influenza hemagglutinin

了解流感血凝素的融合肽突变

• 批准号: 9269426
• 负责人: Peter M Kasson
• 金额: $ 6.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269426
• 关键词: Affect; Antiviral Agents; Antiviral Therapy; Biological Assay; Biological Models; Capsid Proteins; Cell membrane; Cells; Cessation of life; Chimeric Proteins; Coupled; Data; Defect; Development; Elements; Environment; Experimental Models; Goals; Hemagglutinin; Human; Infection; Influenza; Influenza Hemagglutinin; Knowledge; Laboratories; Length; Life; Lipids; Membrane; Membrane Fusion; Membrane Lipids; Methods; Modeling; Modification; Mutagenesis; Mutation; Nature; Outcome; Pathway interactions; Peptides; Performance; Pharmaceutical Preparations; Phenotype; Point Mutation; Process; Proteins; Sterols; Structural Models; Structure; Study models; Testing; Therapeutic Agents; United States; Vesicle; Viral; Virion; Virus; Work; base; influenzavirus; membrane assembly; molecular scale; mutant; novel therapeutics; pathogen; simulation; theories; therapy development

DESCRIPTION (provided by applicant): Influenza is both a major human pathogen, causing approximately 50,000 deaths per year in the United States and a well-studied model system for cell entry by enveloped viruses. Influenza enters cells via a process of membrane fusion, but despite extensive study the mechanism by which influenza hemagglutinin catalyzes this process is not well understood. Experimental mutagenesis has yielded much data on the functional requirements of influenza fusion proteins, but we have no robust theory that could have predicted these results. This proposal seeks to develop a robust understanding of fusion peptide mechanisms sufficient to predict such mutations to hemagglutinin. We also wish to establish which elements of influenza entry are common to all membrane fusion, as modifications to the lipid environment can also promote or block fusion, and which may be virus-specific. We are developing high-performance simulation methods to analyze membrane fusion; in this work, we will use these methods to predict how mutations to influenza fusion peptides alter the virus's ability to infect cells and to investigate how lipid composition changes interact with these mutations to control viral infectivity. Computational predictions will be evaluated against experimental assays performed in the laboratory of collaborator Steinhauer.

描述（由申请方提供）：流感既是一种主要的人类病原体，在美国每年造成约50，000人死亡，也是包膜病毒进入细胞的一种经过充分研究的模型系统。流感病毒通过膜融合过程进入细胞，但尽管进行了广泛的研究，但流感病毒血凝素催化这一过程的机制尚未完全了解。实验诱变已经产生了大量的数据流感融合蛋白的功能要求，但我们没有强大的理论，可以预测这些结果。该提案旨在发展足以预测血凝素突变的融合肽机制的强大理解。我们还希望确定流感病毒进入的哪些元素是所有膜融合所共有的，因为对脂质环境的修饰也可以促进或阻断融合，并且哪些可能是病毒特异性的。我们正在开发高性能的模拟方法来分析膜融合;在这项工作中，我们将使用这些方法来预测流感融合肽的突变如何改变病毒感染细胞的能力，并研究脂质组成的变化如何与这些突变相互作用以控制病毒的感染性。计算预测将根据合作者Steinhauer实验室进行的实验测定进行评估。

项目成果

Influenza hemagglutinin drives viral entry via two sequential intramembrane mechanisms

流感血凝素通过两种连续的膜内机制驱动病毒进入

• DOI: 10.1073/pnas.1914188117
• 发表时间: 2020
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Pabis, Anna;Rawle, Robert J.;Kasson, Peter M.
• 通讯作者: Kasson, Peter M.

Dynamic heterogeneity controls diffusion and viscosity near biological interfaces.

• DOI: 10.1038/ncomms4034
• 发表时间: 2014
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Pronk S;Lindahl E;Kasson PM
• 通讯作者: Kasson PM

Coupled diffusion in lipid bilayers upon close approach.

• DOI: 10.1021/ja508803d
• 发表时间: 2015-01-21
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Pronk S;Lindahl E;Kasson PM
• 通讯作者: Kasson PM

Improving pandemic influenza risk assessment.

• DOI: 10.7554/elife.03883
• 发表时间: 2014-10-16
• 期刊: eLife
• 影响因子: 7.7
• 作者: Russell CA;Kasson PM;Donis RO;Riley S;Dunbar J;Rambaut A;Asher J;Burke S;Davis CT;Garten RJ;Gnanakaran S;Hay SI;Herfst S;Lewis NS;Lloyd-Smith JO;Macken CA;Maurer-Stroh S;Neuhaus E;Parrish CR;Pepin KM;Shepard SS;Smith DL;Suarez DL;Trock SC;Widdowson MA;George DB;Lipsitch M;Bloom JD
• 通讯作者: Bloom JD

Lipid converter, a framework for lipid manipulations in molecular dynamics simulations.

• DOI: 10.1007/s00232-014-9705-5
• 发表时间: 2014-11
• 期刊: JOURNAL OF MEMBRANE BIOLOGY
• 影响因子: 2.4
• 作者: Larsson, Per;Kasson, Peter M.
• 通讯作者: Kasson, Peter M.